Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator

Mammals evolved an endogenous timing system to coordinate their physiology and behaviour to the 24h period of the solar day. While it is well accepted that circadian rhythms are generated by intracellular transcriptional feedback loops, it is still debated which network motifs are necessary and sufficient for generating self-sustained oscillations. Here, we systematically explore a data-based circadian oscillator model with multiple negative and positive feedback loops and identify a series of three subsequent inhibitions known as “repressilator” as a core element of the mammalian circadian oscillator. The central role of the repressilator motif is consistent with time-resolved ChIP-seq experiments of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts.
Author Summary Circadian clocks are endogenous oscillators that drive daily rhythms in physiology, metabolism and behavior. The recent years have witnessed enormous progress in our understanding of the mechanistic and genetic basis of these clocks. While mathematical modelling has made important contributions to our current view of the circadian clock network, it is still debated, which network motifs are necessary and sufficient for generating self-sustained oscillations. Exploiting a data-driven mathematical model we here identify the “repressilator” as a key design principal. The central role of the repressilator motif is consistent with time-resolved binding data of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts.